Summary. Aim: Several studies evaluated the association between rs11077 polymorphism located in the 3’UTR of the XPO5 gene and cancer susceptibility. We conducted a meta-analysis to assess the impact of XPO5 rs11077 polymorphism on cancer risk. Materials and Methods: The online databases were searched for relevant case-control studies published up to July 2018. 15 articles of 16 studies, with totally 7284 cancer cases and 8511 healthy controls, were eligible for inclusion in the meta-analysis. The data were extracted from the eligible studies and were processed using Stata 14.1 and Revman 5.3 software. Pooled estimates of odds ratio with 95% confidence intervals were used to evaluate the strength of association between XPO5 rs11077 and cancer risk. Results: Overall, our finding showed no significant association between XPO5 rs11077 variant and overall cancer risk, either performed subgroup analysis by cancer types and ethnic groups in all genetic model. Conclusion: The findings did not support an association between rs11077 variant and cancer risk. Due to small sample sizes particularly in stratified analysis, further large-scale well designed studies between this polymorphism and cancer risk are warranted.

Cancer is a leading cause of mortality worldwide [1, 2]. There were about 4 292 000 newly-diagnosed cancer cases and 2 814 000 cancer-related deaths in United States in 2017. Although the etiology of cancer is still not clearly disclosed, genetic background and environmental factors are believed to be involved in cancer development [3, 4].

MicroRNAs (miRNAs), as regulators of gene expression, are small single-stranded RNA molecules of about 21–23 nucleotides [5, 6]. The biosynthesis of a functional miRNA involves several miRNA bioge­nesis genes and occurs in multiple steps [7]. The process of miRNA synthesis begins within the nucleus where RNA polymerase II produces large primary miRNA transcripts (about 500 to 3000 nucleotides) known as pri-miRNA. The pri-miRNA is then processed by multiprotein complex that includes DROSHA into pre-miRNA (about 60 to 100 nucleotides). Next, RAN GTPase and exportin-5 (XPO5) complex transfers pre-miRNA to the cytoplasm, and pre-miRNA is then cut into miRNA duplexes by DICER [6, 8] finally forming 18–24 nucleotide single-stranded, mature miRNA [8, 9].

In general, polymorphisms in miRNA processing genes as well as miRNA genes (pri-miRNAs, pre-miRNAs and mature miRNAs) could influence cancer risk by affecting miRNA function [10].

Preceding studies examining the relationship between XPO5 rs11077 gene polymorphism and cancer designated inconclusive findings [11–25]. So, this meta-analysis was performed to evaluate the impact of XPO5 rs11077 polymorphism on cancer risk.

MATERIALS AND METHODS

Literature search. A systemic literature searches in the PubMed, Web of Science, Scopus, and Google Scholar databases was done for all articles focused on association between XPO5 polymorphism and cancer risk published up to June 2018. The search term was “cancer or carcinoma or tumor or neoplasm” and “XPO5 or exportin-5 or miRNA biogenesis” and “polymorphism or mutation or variation or rs11077”.

Inclusion and exclusion criteria. Studies were comprised in the meta-analysis by meeting the following criteria: 1) original case-control studies of the association between the XPO5 rs11077 polymorphism and cancer; 2) studies providing sufficient data of the genotype frequencies of XPO5 rs11077 polymorphism in both cases and controls; 3) the studies have not repeated reports in the same population. The following studies were excluded: 1) conference abstracts, letters, case reports, reviews, overlapped data, animal or mechanism studies for XPO5 rs11077 polymorphism and cancer; 2) studies with insufficient information on genotype frequency. Finally, 15 articles were considered for meta-analysis.

Data extraction. The authors independently extracted data that met the inclusion and exclusion criteria. The following information was collected from each study including the name of first author, year of publication, country, ethnicity, number of cases and controls, and the genotype and allele frequencies of cases and controls.

Statistical analysis.Hardy-Weinberg equilibrium (HWE) for the controls of each study was determined by the chi-square test. We used Revman 5.3 software (Version 5.3. Copenhagen: The Nordic Cochrane Centre, the Cochrane Collaboration, 2014) and STATA 14.1 software (Stata Corporation, College Station, TX, USA) for all statistical analyses and to produce the plots. The strength of the association between XPO5 rs11077 polymorphism and cancer risk was evaluated through calculating pooled odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) using following genetic models: codominant, dominant, recessive, overdominant and allele model. The significance of the pooled OR was determined with the Z-test, and p-values less than 0.05 were considered statistically significant.

Heterogeneity between selected studies was inspected using the I2 statistic and the χ2-based Q test. A p < 0.10 representing the presence of significant hete­rogeneity. When significant heterogeneity values were returned, the random-effects model was used to estimate pooled ORs. Otherwise, the fixed-effects model was employed.

Publication bias across enrolled studies was estimated by Begg’s funnel plot. The degree of asymmetry was assessed using Egger’s linear regression test and p < 0.05 was considered significant publication bias.

Sensitivity analysis was conducted through sequential deleting each of included studies so as to ve­rify the stability of overall estimates.

RESULTS

Fifteen articles [11–25] of 16 studies, with totally 7284 cancer cases and 8511 controls, were eligible for meta-analysis. The main detailed characteristics of the eligible studies are listed in Table 1.

Table 1. Characteristics of the studies eligible for meta-analysis

Author

Year

Country

Ethnicity

Cancer type

Source of control

Genotyping method

Case/ control

Cases

Controls

HWE

AA

AC

CC

A

C

AA

AC

CC

A

C

Buas

2015

Europe

Caucasian

Esophageal cancer

HB

TaqMan

2495/3206

–

–

–

2879

2111

–

–

–

3751

2661

–

Cho

2015

Korea

Asian

Colorectal cancer

HB

PCR-RFLP

408/400

333

74

1

740

76

337

61

2

735

65

0.667

Ding

2013

China

Asian

Non-small cell lung cancer

PCR-LDR

112/80

94

18

0

206

18

65

14

1

144

16

0.803

Horikawa

2008

USA

Caucasians

Renal cell carcinoma

HB

SNPlex

276/277

88

134

54

310

242

89

150

38

328

226

0.044

Kim

2010

Korea

Asian

Lung cancer

HB

Sequencing

100/99

88

12

0

188

12

87

9

3

183

15

< 0.001

Kim

2016

China

Asian

Hepatocellular carcinoma

HB

PCR-RFLP

147/209

128

19

0

275

19

170

38

1

378

40

0.465

Osuch-Wojcikiewicz

2015

Poland

European

Larynx cancer

HB

TaqMan

124/160

36

62

26

134

114

34

44

82

112

208

< 0.001

Sung

2011

Korea

Asian

Breast cancer

HB

TaqMan

559/567

473

82

4

1028

90

501

64

2

1066

68

0.977

Thakkar

2018

India

Asian

Hodgkin Lymphoma

PB

TaqMan

101/200

39

41

21

119

83

76

92

32

244

156

0.638

Wen

2017

China

Asian

Thyroid cancer

HB

TaqMan

1134/1228

907

210

17

2024

244

1023

194

11

2240

216

0.593

Xie

2015

China

Asian

Gastric cancer

HB

PCR-LDR

137/142

119

17

1

255

19

123

18

1

264

20

0.705

Yang

2008

American

Caucasian

Bladder cancer

HB

SNPlex

746/746

248

356

114

852

584

241

363

122

845

607

0.456

Yao

2013

USA

African American

Breast cancer

PB

Illumina GoldenGate

242/411

39

203

–

–

45

214

152

304

518

0.018

Yao

2013

USA

European American

Breast cancer

PB

Illumina GoldenGate

200/310

76

124

–

–

127

130

53

384

236

0.052

Ye

2008

American

Caucasian

Esophageal cancer

HB

SNPlex

340/334

129

150

61

408

272

113

175

46

401

267

0.093

Zhao

2015

China

Asian

Colorectal cancer

HB

PCR-LDR

163/142

143

19

1

305

21

123

18

1

264

20

0.705

Quantitative synthesis. All eligible studies were pooled into the analysis and the results showed that XPO5 rs11077 polymorphism was not associated with the overall cancer risk in codominant, dominant, recessive, overdominant, and allele genetics models (Fig. 1 and Table 2).

Table 2. The pooled ORs and 95% CIs for the association between XPO5 polymorphism and cancer susceptibility

Polymorphism

No

Association test

Heterogeneity

Egger’s testp-value

Begg’s testp-value

OR (95% CI)

Z

p

χ2

I2 (%)

p

Overall cancer

AC vs AA

13

1.04 (0.93–1.15)

0.64

0.52

13.72

13

0.32

0.515

1.00

CC vs AA

13

0.96 (0.68–1.36)

0.23

0.82

22.49

47

0.03

0.916

0.929

AC+CC vs AA

13

1.02 (0.92–1.12)

0.33

0.75

18.82

26

0.17

0.101

0.347

CC vs AC+AA

13

0.95 (0.62–1.46)

0.24

0.81

38.13

69

0.0001

0.940

0.531

AC vs CC+AA

13

1.04 (0.87–1.25)

0.45

0.65

30.80

61

0.002

0.983

0.542

C vs A

14

0.99 (0.88–1.12)

0.14

0.89

34.61

62

0.001

0.423

0.208

GI cancer

AC vs AA

5

0.90 (0.73–1.10)

1.03

0.30

4.87

18

0.30

–

–

CC vs AA

5

1.10 (0.71–1.70)

0.43

0.67

0.80

0

0.94

–

–

AC+CC vs AA

5

9.92 (0.76–1.13)

0.77

0.44

3.80

0

0.43

–

–

CC vs AC+AA

5

1.29 (0.87–1.92)

1.25

0.21

1.18

0

0.88

–

–

AC vs CC+AA

5

0.88 (0.68–1.14)

0.98

0.33

5.79

31

0.22

–

–

C vs A

6

1.03 (0.96–1.10)

0.74

0.46

3.11

0

0.68

–

–

Breast cancer

C vs A

3

1.05 (0.87–1.25)

0.49

0.63

3.96

50

0.14

–

–

Lung cancer

AC vs AA

2

1.05 (0.58–1.88)

0.16

0.88

0.42

0

0.52

–

–

CC vs AA

2

0.18 (0.02–1.58)

1.55

0.12

0.05

0

0.82

–

–

AC+CC vs AA

2

0.90 (0.51–1.58)

0.38

0.70

0.09

0

0.76

–

–

CC vs AC+AA

2

0.18 (0.02–1.56)

1.56

0.12

0.06

0

0.81

–

–

AC vs CC+AA

2

0.75 (0.47–1.20)

1.21

0.23

0.37

0

0.54

–

–

C vs A

2

0.78 (0.46–1.32)

0.91

0.36

0.00

0

0.99

–

–

Asian

AC vs AA

9

1.14 (0.99–1.31)

1.80

0.07

6.75

0

0.56

–

–

CC vs AA

9

1.21 (0.78–1.86)

0.86

0.39

5.29

0

0.73

–

–

AC+CC vs AA

9

1.14 (1.0–1.31)

1.93

0.05

7.30

0

0.50

–

–

CC vs AC+AA

9

1.24 (0.82–1.87)

1.01

0.31

5.20

0

0.74

–

–

AC vs CC+AA

9

1.12 (0.98–1.29)

1.63

0.10

7.55

0

0.48

–

–

C vs A

9

1.06 (1.00–1.13)

1.87

0.06

9.55

16

0.30

–

–

Caucasian

AC vs AA

3

0.89 (0.75–1.05)

1.39

0.16

1.34

0

0.51

–

–

CC vs AA

3

1.08 (0.83–1.40)

0.57

0.57

2.48

19

0.29

–

–

AC+CC vs AA

3

0.93 (0.79–1.09)

0.93

0.35

0.66

0

0.72

–

–

CC vs AC+AA

3

1.20 (0.87–1.65)

1.13

0.26

4.31

0.54

0.12

–

–

AC vs CC+AA

3

0.85 (0.70–1.04)

1.59

0.11

3.16

37

0.21

–

–

C vs A

4

1.02 (0.96–1.09)

0.72

0.47

1.66

0

0.65

–

–

Fig. 1. Flow chart of articles selection for this meta-analysis

We also performed stratified analysis by cancer type and ethnicity (see Table 2). The findings proposed that XPO5 rs11077 was not associated with gastrointestinal cancer, breast cancer and lung cancer. Besides, the variant was not associated with cancer risk in Asian as well as Caucasian population.

Heterogeneity. Heterogeneity among the studies included in the meta-analysis is shown in Table 2. The results showed that heterogeneity exists between the studies in homozygous codominant, recessive, overdominant and allele genetic models. So, random-effects model was used to determine pooled ORs.

DISCUSSION

The etiology of cancer is multifactorial in which both host genetic factors and environmental factors play a role [26, 27]. Accumulating evidence proposed that genetic variation is associated with cancer susceptibility [4, 28]. In this study, we conducted a meta-analysis to evaluate the association between XPO5 rs11077 gene polymorphism and cancer risk based on 16 eligible case-control studies with a total of 7284 cancer cases and 8511 healthy controls. Overall, pooled risk estimates proposed that this polymorphism is not associated with cancer risk. Stratified analyses by cancer types and ethnicities did not support an association between rs11077 polymorphism and cancer susceptibility.

XPO5 gene is mapped to a short arm of chromosome 6 (6p21.1) and encodes XPO5 protein which is involved in export of pre-miRNA from nucleus into the cytoplasm. Hoti et al. [29] reported that a XPO5 knockdown resulted in downregulation of 20 mature miRNAs and overexpression of six miRNAs.

Several studies evaluated the expression levels of XPO5 in various cancers and the findings were controversial. The expression levels of XPO5 were found to be higher in several tumors including breast, ovary, prostate, bladder, and melanoma compared to the normal adjacent tissues, while the lower expression level of XPO5 in kidney, adrenal gland, and hepatocellular carcinoma tumors proposing oncogenic or tumor-suppressor features in different cancer types [29–32].

There are some limitations in our meta-analysis needed to be addressed. First, heterogeneity was observed among the studies possibly resulting from the differences of ethnicity, source of control, and cancer type. Second, this study focused on the effect of rs11077 polymorphism and cancer risk. Gene-gene and gene-environment interactions might also impact in cancer risk. Third, the characteristics of included studies such as age and sex which might affect the results of meta-analysis were not evaluated due to the lack of relevant data across the included studies. Fourth, the majority of the individuals studied were Asian, further studies on other ethnicity groups are needed. Finally, the sample size of our meta-analysis is relatively small especially in subgroup analyses by cancer types (5 studies for gastrointestinal cancer, 3 studies for breast cancer, and 2 studies for lung cancer) and ethnicities (9 studies for Asian and 3 studies for Caucasian). Accordingly, the statistical power of the study is limited and the results should be interpreted with caution.

In conclusion, the results of our meta-analysis based on 16 case-control studies suggested that there is no significant association between the XPO5 rs11077 polymorphism and cancer risk. Statistical power can be improved by pooling analysis from more studies. Considering the limitations mentioned above, further well-designed multicenter studies with large sample sizes, more diverse ethnic groups and cancer types are warranted to verify the findings.